Mechanisms of telomeric instability.

Abstract

Telomeres are the nucleoprotein structures that cap the ends of linear chromosomes. The length of telomeric DNA is an important determinant of function; with short telomeres triggering either replicative senescence or, in the absence of a functional DNA damage response, telomere fusion. Telomere fusion can trigger cycles of anaphase-bridging, breakage and fusion that can lead to genomic arrangements, of the type that are frequently found in cancer. Telomere erosion as a function of ongoing cell division results in the gradual loss of sequences from the terminus; this is superimposed by additional mutational mechanisms that generate large-scale, apparently sporadic, telomeric deletions. These events occur in normal human cells, irrespective of telomerase activity, and because they create telomeres that are capable of fusion, they represent a significant cell-intrinsic mutational mechanism. Here I review some of the potential mechanisms that may result in sporadic telomeric deletion.